According to the enhancement in human living quality, the research of biomineralization is affecting the development of medical field in recent years. It includes the investigation of bone disease mechanism and the therapy strategy, remodel of teeth and treatment of oral disease, moreover, the imagination for abnormal mineralization in the body. Biomineral is a mineral product produced from organism, and contains two mainly inorganic components, carbonate and phosphate, to form hydroxylapatite (HAp) as the basic component of biomineral whose chemical composition is a crystal of Ca10(PO4)6(OH)2. In addition, there are large portions of organic components combined in biominerals.
A molecule whose possess affinity with biomineral, in general, it must has a basic structure to provide calcium binding such as polycarboxylic acid or polyphosphoric acid. After learned from the biological phenomenon, we found that an organism always secretes acid materials to offer an anion for binding with calcium in mineral, and to form biomineral in bone and teeth structure through nucleation. The structure of these acidic materials always contain carboxylic acid rich sequence originally, or derive the functional groups through posttranslational modification such as phosphorylation or sulfation to provide the ability for binding with calcium. These acidic materials may include polysaccaride, proteoglycan and protein.
In literatures, polyaspartic acid is usually to be used as an osteophilic reagent to simulate the natural protein which is rich in aspartic acid. Since polyaspartate is a known mineral binding peptide, and the length of peptide for offering affinity is usually by 6 to 12 aspartic acids. For example, Wang D. et al had published their finding at Bioconjugate Chem. in 2003 and 2007 to explore the comparison of different materials for bone tissue affinity and found that the repeated aspartic acids to form octapeptide presented a good affinity to bone. They conjugated the octapeptide with polymer contained fluorescent substance to observe the fluorescence accumulation in the skeletal system. Furthermore, the application in dentistry was increasing recently. For example, Liu, X.-M. et al had introduced an alendronate as a mineral targeting on cyclodextrins to be used in oral diseases.
According to Ugliengo, P.'s study, that glycine can bind with hydroxylapatite to form a stable complex by its carboxylic group and amino group. However, oxygen atoms in the protein structure play the key functional groups mainly involved in calcium binding in biological system, they may locate on the backbone of protein and water, also on the side chain of aspartic acid, glutamic acid, asparagine and phosphorylated serine. These acidic amino acids offer protein static electricity characteristic, and also affects the binding of calcium directly. The study confirmed that a proper peptide sequence not only provides the selectivity to bind with calcium, also offer biomineral a specific binding and stacking.
Since 1970, Vogtle, F. et al had designed the first synthesized globular dendrimer, which was disclosed that the character of dendrimer molecule is different from the character of a linear polymer. The dendrimer, as implied by the name, is a dendritic macromolecule polymer with a tree like structure. It is highly divergent and has accurate single molecular weight distribution. Different from the traditional linear polymer, its structure is showed in three-dimensional radial arrangement beginning from the core and extending to the outward evenly. When reaches branch point of the first layer, it is defined as the first generation. Generation is defined as the numbers of branch points from a core toward outer shell, and based on the branch point between the same layer as calculate basis. The structure from branch point to next layer is called a generation. When there are five intersection points, it represents a fifth generation dendrimer. The cartoon of dendrimer is shown in FIG. 1, if it has a core only, it will be called the zero generation, and has no intersection in such a structure.
The known dendrimer such as polyamindoamine dendrimer (PAMAM), polyester type dendrimer, polyglycerol dendrimer, triazine based dendrimer, Poly(propylene imine) dendrimer, Newkome-type dendrimers, poylylsine dendrimer, and other mixed type can be applied.
The dendrimer utilized its divergent structure characters and self-assembly behavior to achieve many performances that were much different from small molecules did. Once an interaction between single small molecule and its interaction part is not strong originally, to shorten their distance will generally be an opportunity to increase interaction. Alternatively, the poorness of interaction will be overcome by increasing numbers of the small molecules exposed to the interaction part. Therefore, the binding ability can be improved through multivalent effect of divergent molecule. Currently, there are many reports in biomaterial field including drug release, gene therapy, cell membrane penetration, cell structure controlling, and medical imagining.
In this invention, monomer aspartic acid or polyaspartate will be incorporated on divergent frameworks to assess better binding affinity. In this composition, positive charge by aspartic acid will chelate at the biomineral surface, and the divergent backbone will additionally offer multivalent binding. According to the report by Percec, V., topology arrangement that have plenty of functional groups in binding area will be a perfect approach to present aspartic acid on the surface of distributed backbone to perform divergent peptides in the present invention. It may offer more prominent mineral affinity ability because of their multivalent binding strategy.